Widespread microRNA repression by Myc contributes to tumorigenesis

Chang, Tsung Cheng; Yu, Duonan; Lee, Yun Sil; Wentzel, Erik A.; Arking, Dan E.; West, Kristin M.; Dang, Chi V.; Thomas-Tikhonenko, Andrei; Mendell, Joshua T.

doi:10.1038/ng.2007.30

Cited by 1,205 publications

(1,192 citation statements)

References 51 publications

Supporting

Mentioning

1,086

Contrasting

Unclassified

Order By: Relevance

“…Whether and how c-myc and TCL1 cooperate toward the development of BL is, however, not known. A recent study with an inducible c-myc experimental system identified that it contributes to tumorigenicity by suppressing tumor suppressor miRs (Chang et al, 2008). Interestingly, a majority of those miRs repressed by c-myc, including miR-29b and miR-146a, were seen upregulated by LMP1 in our study.…”

Section: Discussionsupporting

confidence: 60%

See 1 more Smart Citation

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

et al. 2009

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) encoded latent membrane protein 1 (LMP1) is noted for its transforming potential. Yet, it also acts as a cytostatic and growth-relenting factor in Burkitt's lymphoma (BL) cells. The underlying molecular mechanisms of the growth inhibitory property of LMP1 have remained largely unknown. In this study, we show that LMP1 negatively regulates a major oncogene, TCL1, in diffuse large B-cell lymphoma (DLBCL) and BL cells. MicroRNA (miR) profiling of LMP1 transfectants showed that among others, miR-29b, is upregulated. LMP1 diminished TCL1 by inducing miR29b through C-terminus activation region 1 (CTAR1) and CTAR2. miR-29b locked nucleic acid (LNA) antisense oligonucleotide transfection into LMP1-expressing cells reduced miR-29b expression and consequently reconstituted TCL1, suggesting that LMP1 negatively regulates TCL1 through miR-29b upregulation. The miR-29b increase by LMP1 was due to an increase in the cluster pri-miR-29b1-a transcription, derived from human chromosome 7. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase-activating function of LMP1 is important for this effect. The ability of LMP1 to negatively regulate TCL1 through miR-29b might underlie its B-cell lymphoma growth antagonistic property. As LMP1 is also important for B-cell transformation, we suggest that the functional dichotomy of this viral protein may depend on a combination of levels of its expression, lineage and differentiation of the target cells and regulation of miRs, which then directs the outcome of the cellular response.

show abstract

Section: Discussionsupporting

confidence: 60%

“…In this study, we show that LMP1 can simultaneously induce several miRs with noted tumor inhibitory capacity and suppress tumor-promoting miRs (He et al, 2005;O'Donnell et al, 2005;Chang et al, 2008). Furthermore, we identified that LMP1, through its CTAR1 and CTAR2 domains, activates miR-29b expression to regulate TCL1 oncogene.…”

Section: Discussionmentioning

confidence: 69%

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Therefore, we performed a pulse‐chase labeling experiment, which revealed a strongly enhanced TSC1 mRNA turnover in low MYC (+Tet) compared to high MYC (−Tet) P493‐6 cells (Fig 5C), indicating that MYC function stabilizes the TSC1 mRNA. Since MYC is a known regulator of microRNA (miRNA) expression (Chang et al , 2008), we examined whether the observed increase in mRNA turnover in response to MYC repression may be caused by miRNA regulation, which generally results in deadenylation and decay of target mRNAs. In search of potentially involved miRNAs, we identified conserved binding sites for the MYC‐suppressed miRNAs miR‐15a/16‐1, ‐22, ‐23ab ‐26ab, ‐29abc, ‐30e‐5p, and ‐195 in the 3′untranslated region (3′UTR) of the TSC1 mRNA by using the TargetScan algorithm (http://www.targetscan.org).…”

Section: Resultsmentioning

confidence: 99%

“…MiR‐15a and miR‐16‐1 have identical seed sequences and reside in the DLEU2 / miR‐15a/16‐1 cluster in the chromosomal region 13q14 whose deletion is commonly associated with the B‐cell malignancy chronic lymphocytic leukemia (B‐CLL; Klein et al , 2010). It was shown by others that MYC represses pri‐microRNA 15a/16‐1 transcription in P493‐6 cells through direct interaction with the pri‐microRNA promoter (Chang et al , 2008). Accordingly, we found that induction of MYC reduced miR‐15a levels in P493‐6 cells (Fig 5D).…”

Section: Resultsmentioning

confidence: 99%

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

et al. 2018

View full text Add to dashboard Cite

The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient‐sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC‐driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR‐15a. TSC1 knockdown results in elevated mTORC1‐dependent mitochondrial respiration enhanced ROS production and apoptosis. Moreover, TSC1 deficiency attenuates tumor growth in a xenograft mouse model. Our study reveals a novel role for TSC1 in securing homeostasis between MYC and mTORC1 that is required for cell survival and tumor maintenance in Burkitt's lymphoma. The study identifies TSC1/2 inhibition and/or mTORC1 hyperactivation as a novel therapeutic strategy for MYC‐driven cancers.

show abstract

“…The cooperating effects of MYC and BCL2 in lymphomagenesis have been shown in many studies. [4][5][6][7][8][9][10][11][12][13][14] Numerous case series of MYC/BCL2 double-hit lymphoma are reported in the literature. [15][16][17][18][19][20][21][22][23][24] MYC/ BCL2 DHLs represent B10% of all lymphomas that otherwise resemble diffuse large B-cell lymphoma (DLBCL).…”

mentioning

confidence: 99%

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Seegmiller

Lin

et al. 2015

Modern Pathology

View full text Add to dashboard Cite

Large B-cell lymphomas with IGH@BCL2 and MYC rearrangement, known as double-hit lymphoma (DHL), are clinically aggressive neoplasms with a poor prognosis. Some large B-cell lymphomas have concurrent abnormalities of MYC and BCL2 other than coexistent translocations. Little is known about patients with these lymphomas designated here as atypical DHL. We studied 40 patients of atypical DHL including 21 men and 19 women, with a median age of 60 years. Nine (23%) patients had a history of B-cell non-Hodgkin lymphoma. There were 30 diffuse large B-cell lymphoma (DLBCL), 7 B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma, and 3 DLBCL with coexistent follicular lymphoma. CD10, BCL2, and MYC were expressed in 28/39 (72%), 33/35 (94%), and 14/20 (70%) cases, respectively. Patients were treated with standard (n ¼ 14) or more aggressive chemotherapy regimens (n ¼ 17). We compared the atypical DHL group with 76 patients with DHLand 35 patients with DLBCL lacking MYC and BCL2 abnormalities. The clinicopathologic features and therapies were similar between patients with atypical and typical DHL. The overall survival of patients with atypical double-hit lymphoma was similar to that of patients with double-hit lymphoma (P ¼ 0.47) and significantly worse than that of patients with DLBCL with normal MYC and BCL2 (P ¼ 0.02). There were some minor differences. Cases of atypical double-hit lymphoma more often have DLBCL morphology (Po0.01), less frequently expressed CD10 (Po0.01), and patients less often had an elevated serum lactate dehydrogenase level (P ¼ 0.01). In aggregate, these results support expanding the category of MYC/ BCL2 DHL to include large B-cell lymphomas with coexistent MYC and BCL2 abnormalities other than concurrent translocations.

show abstract

Widespread microRNA repression by Myc contributes to tumorigenesis

Cited by 1,205 publications

References 51 publications

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

Epstein–Barr virus encoded LMP1 downregulates TCL1 oncogene through miR-29b

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

B-cell lymphomas with concurrent MYC and BCL2 abnormalities other than translocations behave similarly to MYC/BCL2 double-hit lymphomas

Contact Info

Product

Resources

About